Pharmacology of Hormonal

contraception

Dr.Siti Syarifah
Dan
Drs.Wakidi Msi, Apt

Dept.Farmakologi & Therapeutik

Fak.Kedokteran USU
MEDAN
 Contraception
• Male and female • Intrauterine system
condoms • Sterilisation
• Intrauterine device • Natural family
• Diaphragms and planning
caps • Combined pill
• Contraceptive • Progestogen-only
injection pill
• Contraceptive • Emergency
implant contraception
• Contraceptive
patch
Hormonal =Prevents ovulation
=Thickens mucus at the cervix
so sperm cannot pass through
=Changes the environment of the
uterus and fallopian tubes to
prevent fertilization or implantation
should fertilization occur
 Oral Contraception

Combined oral
contraception (COC)
Progestogen only pill
(POP)
Emergency Hormonal
Contraception (EHC)
 Combined Oral Contraception
• Contains oestrogen
and progestogen
• Most effective
preparation for
• Take one tablet general use
daily for 21 days (28 • With optimal use,
> 99% effective
for ED) followed by
a 7 day pill free
period
 Hormonal Contraception Options
• Combined oral contraceptives (COC)
– (Mestranol)→ethinyl estradiol
• Estrogen level has decreased from 100 mcg/day
→ as low as 20 mcg/day
• Most women should get no more than 35
mcg/day ethinyl estradiol
• 50 mcg estrogen may be appropriate if:
–Spotting, absence of bleeding, or
dysfunctional uterine bleeding; Acne; Ovarian
cysts; Endometriosis; Drug interactions
(induction of Cytochrome P450)
 Hormonal Contraception Options
= 50 mcg estrogen may be appropriate if:
–Spotting, absence of bleeding, or dysfunctional
uterine bleeding; Acne; Ovarian cysts;
Endometriosis; Drug interactions (induction of
Cytochrome P450)

Note:
= EE in HRT= >0.625 mg===625mcg/day
= In oral contraceptive :25-50 mcg/day
 Hormonal Contraception Options
• Two types of estrogen are used
in combined OCs:
ethinyl estradiol and mestranol.
• Mestranol is a “prodrug” that is
converted in vivo to ethinyl estradiol.
• Several different progestins,
of varying degrees of progestational
potency, are used in combined OCs.
Hormonal Contraception Options
– Progestins
• Most potent: desogestrel, levonorgestrel,
norgestrel
• Least potent: norethindrone
• Most androgenic: norgestrel > norethindrone
& ethynodiol
• Least androgenic: desogestrel & norgestimate
→ may ↓ risk of MI
 Formulations
• Formulations may be :
1. Monophasic (each tablet contains a fixed
amount of estrogen and progestin);
2. Biphasic (each tablet contains a fixed amount
of estrogen, while the amount of progestin
increases in the second half of the cycle); or
3. Triphasic (the amount of estrogen may be
fixed or variable, while the amount of
progestin increases in 3 equal phases).
 Hormonal Contraception Options cont’d.
• Monophasic vs. biphasic vs. triphasic

– Biphasic and triphasic thought to more closely

mimic fluctuations in estrogen and progesterone
levels during the menstrual cycle; ------
– ↓ dose-dependent adverse effects of progestin

– Recent Cochrane reviews conclude that choice of

progestin is more important than phasic
formulation
 Hormonal Contraception Options (cont’d.)
• Progestin-only pills (POP)
– Women who are breastfeeding-can be started immediately
postpartum
– Considered safer in :
= women w/ migraines,
=hx of thromboembolic disease,
= poorly controlled HTN w/ vascular disease or
= >35 yrs, diabetes w/ vascular disease or
= >35 yrs, SLE w/vasculardisease,hypertriglyceridemia,
smoker over 35 yrs of age, CAD, CHF,
cerebrovascular disease
 How does hormonal contraception
work?
• Estrogen:
– Prevention of estrogen surge, which prevents LH surge →
no ovulation
– Suppression of gonadotropin secretion during follicular
phase, preventing follicular maturation and preventing
ovarian hormone production
• Progesterone:
– Creates thick cervical mucus to hinder sperm penetration
– Impairs normal tubal motility and peristalsis

» Martin KA, Barbieri R, Up To Date: Overview of

the use of estrogen-progestin contraceptives.
Available online. (Accessed Jan 30 2007).
Combined Oral Contraception
How does it work?
 Mechanism of action
• Combined :
most effective method because they inhibit midcycle
gonadotropin surge and prevent ovulation
• Progestin only pills:
don’t mainly not inhibit ovulation
Both types act by -altering cervical mucus making it
thick viscid and scanty
-alter endometrium so not fit for
implantation
- alter ovarian responsiveness to
gonadotropin stimulation
Composition of
Various
Combination
Hormonal
Contraceptives
 INDICATIONS
• The use of condoms is still
recommended in combined OC
users for protection against
sexually transmitted infections
(STIs) and human
immunodeficiency virus (HIV).
• (Note:bagi penganut free-sex)
 CONTRAINDICATIONS
• The World Health Organization
(WHO)
has developed a list of
absolute and relative
contraindications
to the use of combined OCs,
based on the available
evidence of risks
WHO category
 ABSOLUTE CONTRAINDICATIONS
1. < 6 weeks postpartum if breastfeeding
2. Smoker over the age of 35 (≥ 15 cigarettes per day)
3. Hypertension (systolic ≥ 160mm Hg or diastolic ≥ 100mm Hg)
4. Current or past history of venous thromboembolism (VTE)
5. Ischemic heart disease
6. History of cerebrovascular accident
7. Complicated valvular heart disease
8. Migraine headache with focal neurological symptoms
9. Breast cancer (current)
10. Diabetes with retinopathy/nephropathy/neuropathy
11. Severe cirrhosis
12. Liver tumour (adenoma or hepatoma)
 RELATIVE CONTRAINDICATIONS
1. Smoker over the age of 35 (< 15 cigarettes per day)
2. Adequately controlled hypertension
3. Hypertension (systolic 140–159mm Hg,
diastolic 90–99mm Hg)
4. Migraine headache over the age of 35
5. Currently symptomatic gallbladder disease
6. Mild cirrhosis
7. History of combined OC-related cholestasis
8. Users of medications that may interfere with
combined OC metabolism
 NON-CONTRACEPTIVE BENEFITS
1. Cycle regulation
2. Decreased menstrual flow
3. Increased bone mineral density
4. Decreased dysmenorrhea
5. Decreased peri-menopausal symptoms
6. Decreased acne
7. Decreased hirsutism
8. Decreased endometrial cancer
9. Decreased ovarian cancer
10. Decreased risk of fibroids
11. Possibly fewer ovarian cysts
12. Possibly fewer cases of benign breast disease
13. Possibly less colorectal carcinoma
14. Decreased incidence of salpingitis
15. Decreased incidence or severity of moliminal symptoms
 Side effects
• Most are minor SE
• Breakthrough bleeding
• Mood change
• Fluid retention
• Nausea/vomitting ==patch
• Headache
• Mastalgia
• Loss of libido
• May improve or disappear within 3-6 mo
 Breakthrough bleeding
• Endometrial instability
• Fluctuation between:
• The peaks after absorption
• The trough before the next dose
• Spontaneous resolve in few months
• A different formulation
• Alternative P or ↑ dose of P
• Biphasic pills
• A higher dose of E
 Drug interactions
• Reduce the efficacy of COC
• 2 ways:
=Induction of liver enzymes
- ↑ metabolism and elimination of both E and P
e.g. anticonvulsants, antituberculosis,fenobarbital
= Effect on entero-hepatic circulation:
= extensive 1st pass metabolism (glucoronide
form)
 Drug Interactions
• The effectiveness of COC, POP and EHC
will be reduced by interaction with drugs
that are enzyme inducers

• Broad spectrum antibiotics may reduce

effectiveness of COC by altering the
bacterial flora of the bowel
• (Bowel flora able to remove glucoronide and
restore EE for reabsorption)
 Which pill?
• Lowest dose of E and P
• Provides effective contraception
• Produces acceptable cycle control
• Fewest side effects
• Least effect on carbohydrate and lipid
• metabolism and haemostatic parameters
• Individualized:
- Variation in circulating hormone level, endorgan
-sensitivity, tolerance of side effects and
• desire to continue the pills
 Progestogen only pill

• Contains one active ingredient -

progesterone
• Taken continuously – no break
• Offers an alternative when
oestrogens are contraindicated
• Efficacy dependent on the
meticulousness of the user
 Depo-Provera:
• Inhibits Ovulation
• 150 mg q 3months (14 day grace period)
• Delayed Ovulation After Discontinuation
• Main Side-Effects:
• -- menorhagie
– Amenorrhea
– Weight Gain
– Hair Loss
– Libido decrease
 Norplant:
• Implantable for ≤ 5 Years
• Similar Side Effects as Depo-Provera
• Avg. Yearly Failure Rate: 0.8/100 (Increases :
> 2/100 after 5 years)
• Occasionally Difficult to Remove
 Comparison of Oral Contraceptives
• Low-dose Monophasic Pills
– Nordette, Low Ogestrel: low estrogen, medium progestin,
medium/high androgen
– Loestrin Fe 1.5/30: low estrogen, high progestin, high androgen
– Ortho-Cept: low estrogen, high progestin, low androgen
– Yasmin: low estrogen, progestin unclear, anti-androgenic and
anti-mineralcorticoid
– Demulen 1/35: medium estrogen, high progestin, low androgen
– Ortho-Cyclen, Ovcon-35, Modicon: medium estrogen, low
progestin, low androgen
– Ortho-Novum 1/50, Ortho-Novum 1/35: medium estrogen, medium
progestin, medium androgen

====lihat di MIMS

» Hormonal contraception. Pharmacist’s Letter/Prescriber’s Letter 2006; 22 (8):220809.

 Comparison Cont’d.
• High-dose Monophasic Pills
– Ovcon-50: high estrogen, medium progestin,
medium androgen
– Ogestrel 0.5/50: high estrogen, high progestin,
high androgen
– Demulen 1/50: high estrogen, high progestin,
medium/high androgen

====lihat di MIMS
» Hormonal contraception. Pharmacist’s Letter/Prescriber’s Letter 2006; 22
(8):220809.
 Comparison Cont’d.
• Biphasic Pills
– Mircette: low estrogen, high progestin, low
androgen
– Ortho-Novum 10/11: high estrogen, medium
progestin, low/medium androgen

» Hormonal contraception. Pharmacist’s Letter/Prescriber’s Letter 2006; 22

(8):220809.

====lihat di MIMS
 Comparison Cont’d.
• Triphasic Pills
– Estrostep Fe: low estrogen, high progestin, medium androgen
– Ortho Tri-Cyclen Lo: low estrogen, low progestin, low androgen
– Cyclessa: low estrogen, high progestin, low androgen
– Triphasil: medium estrogen, low progestin, low/medium
androgen
– Ortho Tri-Cyclen: medium estrogen, low progestin, low
androgen
– Tri-Norinyl, Ortho-Novum 7/7/7: medium estrogen, medium
progestin, low/medium androgen
» Hormonal contraception. Pharmacist’s Letter/Prescriber’s Letter 2006; 22 (8):220809.

====lihat di MIMS
 Emergency Hormonal Contraception

• Levonelle 1500 (one step)

• Contains high dose progesterone
(levonorgesterel)
• One 1500mcg tablet taken as soon as
possible after unprotected intercourse
(up to 72 hours after)
• Preferably within 12 hours, no later than
72 hours
 Emergency Hormonal Contraception
( EHC)
• Taking the dose as soon as possible
increases efficacy
• Available from:
– A&E
– GP
– Walk in Centres
– Family Planning Clinics
– Sexual Health Clinics
– Community Pharmacies
 Emergency Contraception (ECP)
• Progestin-only (preferred)
• – “Plan B” (levonorgestrel 0.75 mg)
• – Now OTC (behind the counter)
• 1 tablet q 12 hours x 2 (FDA approved labeling)
• 89% decrease in risk of pregnancy (1% vs 8%)
• Data shows can take second pill up to 24 hr after 1st
• Data shows can take 2 pills once (1.5 mg)
• – MUST TELL PT PACKAGE INSTRUCTIONS DIFFERENT!
• Data shows may take up to 5 days post-intercourse
• (3-5 days: efficacy 63%)
 When is EHC indicated?
• Unprotected sexual intercourse
• Reduced efficacy of other forms of
contraception:
– Torn, leaking condom
– Missed pills
– Late implant or injection
– Detached contraceptive patch
 How does EHC work?
• Dependent on point in the menstrual
cycle
• Either prevents or delays ovulation,
prevents fertilisation or prevents
implantation of the fertilised egg into the
uterus.
• Clinical opinion is that EHC is not an
abortifacient
 Missed Contraceptive Pills
• COC
– 7 days of pill taking put the ovaries to sleep
– More than 7 days since pill taking may wake the
ovaries up
– 7 pill free days are safe

• POP
– Not for the forgetful!!!!!
 Missed COC Pill/s
Missed COC pill

Less than 12 hours elapsed More than 12 hours elapsed

Take missed pill and continue regime as Where in pill cycle?

normal. No extra precautions required

1 pill missed from a pack 2 or more pills missed from

in the cycle 2 or more pills missed at any days 15-21
time in the cycle

Continue COC Continue COC to end of pack Continue COC and use
use extra precautions for 7 extra precautions for 7
days days. GO straight on to
next pack without a break
 Missed POP Pill/s
Missed POP pill/s

More than 3 hours late

Less than 3 hours late? (27 hours after last pill)

Cerazette?
Take the missed pill and
continue as normal

NO YES

Less than More than

12 hours late? 12 hours late?
Take missed pill as soon as
possible,
Take rest of packet as normal
And use extra precautions for the
next 2 days

Take missed pill as soon as

Take missed pill as soon possible, take the rest of the packet
as possible and continue as normal.
with packet as normal Use extra precautions until pills
taken for 2 consecutive days
 Side Effects
Too much ESTROGEN Nausea, bloating, breast
tenderness, ↑ BP, melasma,
headache
Too little ESTROGEN Early/mid-cycle breakthrough
bleeding, ↑ spotting,
hypomenorrhea
Too much PROGESTIN Breast tenderness, headache,
fatigue, changes in mood

Too little PROGESTIN Late breakthrough bleeding

Too much ANDROGEN ↑ appetite, wt gain, acne, oily skin,

hirsutism, ↓ libido, breast
tenderness, ↑ LDL, ↓ HDL
Hormonal contraception. Pharmacist’s Letter/Prescriber’s Letter 2006; 22
(8):220809.
 Other benefits (lowered risk or incidence):

• Dysmenorrhea
• Iron deficiency anemia
• Ectopic pregnancy (COC pill only)
• Ovarian cysts (higher dose estrogen pills only)
• Ovarian cancer
• Endometrial cancer
• Increased bone density
• Acne
– Ortho Tri-Cyclen and Estrostep FDA-labeled for treatment of acne*

» Martin KA, Barbieri R, Up To Date: Overview of the use of estrogen-progestin

contraceptives. Available online. (Accessed Jan 30 2007).
» *Hormonal contraception. Pharmacist’s Letter/Prescriber’s Letter 2006; 22
(8):220809.
 Vomiting & Diarrhoea

• If vomiting within 3 hours of

taking pill then absorption will be
reduced and may be ineffective.
• Diarrhoea alone without vomiting
has to be severe to reduce the
absorption of the pill.
 Absolute Contraindications
• Known pregnancy
• Breast or uterine cancer
• Thromboembolic event or stroke
• Hepatitis
CONTRACEPTIVE
COMPLIANCE

--Correct use
--Consistent use
--Continuing use
 Learning Outcomes

1. Be familiar with different types of oral

contraceptives
2. Understand how emergency hormonal
contraception (EHC) and oral
contraceptives work
3. Gather necessary information to be able to
clarify the question
4. Interpret information about contraceptives
and turn it into appropriate advice
Thank you for the attention